TY - JOUR
T1 - MEF2C Hypofunction in Neuronal and Neuroimmune Populations Produces MEF2C Haploinsufficiency Syndrome–like Behaviors in Mice
AU - Harrington, Adam J.
AU - Bridges, Catherine M.
AU - Berto, Stefano
AU - Blankenship, Kayla
AU - Cho, Jennifer Y.
AU - Assali, Ahlem
AU - Siemsen, Benjamin M.
AU - Moore, Hannah W.
AU - Tsvetkov, Evgeny
AU - Thielking, Acadia
AU - Konopka, Genevieve
AU - Everman, David B.
AU - Scofield, Michael D.
AU - Skinner, Steven A.
AU - Cowan, Christopher W.
N1 - Publisher Copyright:
© 2020 Society of Biological Psychiatry
PY - 2020/9/15
Y1 - 2020/9/15
N2 - Background: Microdeletions of the MEF2C gene are linked to a syndromic form of autism termed MEF2C haploinsufficiency syndrome (MCHS). MEF2C hypofunction in neurons is presumed to underlie most of the symptoms of MCHS. However, it is unclear in which cell populations MEF2C functions to regulate neurotypical development. Methods: Multiple biochemical, molecular, electrophysiological, behavioral, and transgenic mouse approaches were used to characterize MCHS-relevant synaptic, behavioral, and gene expression changes in mouse models of MCHS. Results: We showed that MCHS-associated missense mutations cluster in the conserved DNA binding domain and disrupt MEF2C DNA binding. DNA binding–deficient global Mef2c heterozygous mice (Mef2c-Het) displayed numerous MCHS-related behaviors, including autism-related behaviors, changes in cortical gene expression, and deficits in cortical excitatory synaptic transmission. We detected hundreds of dysregulated genes in Mef2c-Het cortex, including significant enrichments of autism risk and excitatory neuron genes. In addition, we observed an enrichment of upregulated microglial genes, but this was not due to neuroinflammation in the Mef2c-Het cortex. Importantly, conditional Mef2c heterozygosity in forebrain excitatory neurons reproduced a subset of the Mef2c-Het phenotypes, while conditional Mef2c heterozygosity in microglia reproduced social deficits and repetitive behavior. Conclusions: Taken together, our findings show that mutations found in individuals with MCHS disrupt the DNA-binding function of MEF2C, and DNA binding–deficient Mef2c global heterozygous mice display numerous MCHS-related phenotypes, including excitatory neuron and microglia gene expression changes. Our findings suggest that MEF2C regulates typical brain development and function through multiple cell types, including excitatory neuronal and neuroimmune populations.
AB - Background: Microdeletions of the MEF2C gene are linked to a syndromic form of autism termed MEF2C haploinsufficiency syndrome (MCHS). MEF2C hypofunction in neurons is presumed to underlie most of the symptoms of MCHS. However, it is unclear in which cell populations MEF2C functions to regulate neurotypical development. Methods: Multiple biochemical, molecular, electrophysiological, behavioral, and transgenic mouse approaches were used to characterize MCHS-relevant synaptic, behavioral, and gene expression changes in mouse models of MCHS. Results: We showed that MCHS-associated missense mutations cluster in the conserved DNA binding domain and disrupt MEF2C DNA binding. DNA binding–deficient global Mef2c heterozygous mice (Mef2c-Het) displayed numerous MCHS-related behaviors, including autism-related behaviors, changes in cortical gene expression, and deficits in cortical excitatory synaptic transmission. We detected hundreds of dysregulated genes in Mef2c-Het cortex, including significant enrichments of autism risk and excitatory neuron genes. In addition, we observed an enrichment of upregulated microglial genes, but this was not due to neuroinflammation in the Mef2c-Het cortex. Importantly, conditional Mef2c heterozygosity in forebrain excitatory neurons reproduced a subset of the Mef2c-Het phenotypes, while conditional Mef2c heterozygosity in microglia reproduced social deficits and repetitive behavior. Conclusions: Taken together, our findings show that mutations found in individuals with MCHS disrupt the DNA-binding function of MEF2C, and DNA binding–deficient Mef2c global heterozygous mice display numerous MCHS-related phenotypes, including excitatory neuron and microglia gene expression changes. Our findings suggest that MEF2C regulates typical brain development and function through multiple cell types, including excitatory neuronal and neuroimmune populations.
KW - Autism
KW - Mef2c
KW - Microglia
KW - Mouse
KW - Neurodevelopmental disorder
KW - Neuron
UR - http://www.scopus.com/inward/record.url?scp=85084565209&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85084565209&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2020.03.011
DO - 10.1016/j.biopsych.2020.03.011
M3 - Article
C2 - 32418612
AN - SCOPUS:85084565209
SN - 0006-3223
VL - 88
SP - 488
EP - 499
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 6
ER -